GENERAL INTRODUCTION: PRION DISEASES

Introduction

A new disease in cattle that did not respond to any treatment was first observed on a farm in England in April 1985, which was initially termed chronic hypersensitivity and incoordination syndrome in the absence of any pathological diagnosis.¹²⁰ The farm experienced a further nine cases over a two year period, of which three were submitted to the Central Veterinary Laboratory for further investigation. These cases and others submitted at around the same time resulted in the discovery of a novel progressive disease, bovine spongiform encephalopathy (BSE), in cattle,¹¹⁴ characterized by grey matter vacuolation and presence of fibrils in the brain. Similar pathological changes had previously been known to occur naturally only in sheep and goats with scrapie and deer and elk as a result of chronic wasting disease, caused by unconventional infectious agents. Epidemiological investigations soon traced the source of infection to the feeding of contaminated meat and bone meal (MBM),¹²⁵ which was subsequently prohibited to eradicate the disease. More than 170,000 cattle have been affected in the United Kingdom (UK) alone but the disease was also detected in other European countries as well as the USA, Canada and Japan. In 1996, a new human spongiform encephalopathy (variant Creutzfeldt-Jakob disease, vCJD) was reported in the UK,¹²⁶ which was clinically and pathologically distinct from the sporadic form that has an incidence of approximately 1.5-2 per million people across the world. The similarities in the biological properties of the infectious agent when brain from affected humans and cattle were transmitted into mice¹⁸ suggested that the agent was the same and that BSE, or popularly named “mad cow disease”, was a zoonosis. Over 170 vCJD cases have been diagnosed in the UK to date, with considerably fewer cases in other countries,⁷⁸ some with a history of residence in the UK.

The BSE epidemic had a huge economic impact on the UK and other countries because of restrictions on trade and export of animals and derived products. The European Union introduced legislation in 2001 that required the testing of healthy slaughtered and fallen cattle for BSE. This testing regime identified two additional types of BSE in Europe,^{13, 23} which were distinct from the common form of BSE, now termed classical BSE (C-type BSE), and separated into H-type and L-type BSE based on the lower and higher molecular mass of the unglycosylated protein fragment detectable when brain samples were subjected to proteinase digestion and Western immune-blotting. The aetiology of these atypical BSE forms remains unknown but their rare occurrence (less than 1 per 1,000,000 tested adult cattle) in cattle aged predominantly 8 years or older, is suggestive of a spontaneous disease.¹¹² It is not yet known whether these atypical BSE strains are also zoonotic but transmissions of L-type BSE to non-human primates^{26, 91} have been reported although they did not resemble any known form of CJD in humans based on studies in human transgenic mice.⁶⁰

Aetiology

Bovine spongiform encephalopathy is associated with the presence of an abnormal isoform of a naturally occurring host protein (cellular prion protein, PrP^C), which is resistant to proteolysis. It is now commonly accepted that the infectious agent is a proteinaceous infectious particle or prion,⁹⁵ which induces a switch from an alpha-helical PrP^C to a proteinase-resistant beta-sheet conformation. Multiple conformations may exist, resulting in different strains. These strains are usually identified by inoculating tissues from animals affected by transmissible spongiform encephalopathies (TSEs) into mice. The incubation time and the degree of vacuolation (vacuolation score) in specific areas of the brain in a group of diseased mice are then used to characterize the strain.¹⁷ The BSE strain responsible for the BSE epidemic appears to be unique and stable, even when transmitted to other susceptible species⁴⁴ and resembles that of vCJD in mice.⁹⁶

Questions still remain about the origin of the BSE strain causing the BSE epidemic. It may have been a specific ovine scrapie strain that was transmitted from sheep to cattle, a scrapie-derived strain that was modified in cattle during recycling in MBM, a spontaneous genetic mutation in cattle or strain originating from a non-ruminant mammalian species.^{94, 125} Intracerebral inoculation of cattle with pools of scrapie-affected sheep brains have failed to reproduce a BSE-like disease^{24, 29, 72, 97} and oral challenge did not produce disease at all^{28, 76} but other untested scrapie strains may exist that are pathogenic for cattle.

The discovery of atypical BSE has led to the identification of two additional BSE strains that are naturally occurring in cattle and distinct in their pathological, molecular and biological phenotype, which were termed...